The Gastrin-releasing Peptide Receptor (GRPR), a member of the G protein-coupled receptors (GPCRs), binds to ligands like gastrin-releasing peptide (GRP) [3]. GRP/GRPR signalling is involved in multiple biological processes, including the regulation of brain functions such as memory, cognition, fear, and circadian rhythms [1]. It is also associated with pathophysiological processes of various diseases, including inflammatory, cardiovascular, neurological diseases, and cancers [3].

In alcohol-associated liver injury (ALI), Grpr -/- and Grprflox/floxLysMCre mice showed alleviated ethanol-induced liver injury, suggesting that GRPR plays a pro-inflammatory and oxidative stress role in ALI, potentially via the IRF1-mediated Caspase-1 inflammasome and NOX2-dependent reactive oxygen species pathway [2]. In hyperuricemia-induced renal inflammation and fibrosis, GRPR knockout or conditional knockout in renal tubular epithelial cells significantly alleviated the decline in renal function and fibrosis in HN mice, indicating that GRPR enhances such injury via ABCG2-dependent mechanisms [4]. In acute kidney injury (AKI), genetic deletion of GRPR protected mice from cisplatin-and ischemia-induced AKI, and GRPR was found to interact with Toll-like receptor 4 to activate STAT1, leading to tubular epithelial cell necroptosis, necroinflammation, and macrophages recruitment [5].

In conclusion, GRPR is involved in regulating multiple biological functions and is pathogenic in diseases like ALI, hyperuricemia-induced renal injury, and AKI. Gene knockout and conditional knockout mouse models have been crucial in revealing these roles, providing potential therapeutic targets for these disease areas.

References:

1. Zhao, Tiantian, Chen, Aiwen, Dai, Danqing, Gao, Xiao-Fei, Xiong, Lize. 2023. Role of the GRP/GRPR System in Regulating Brain Functions. In ACS chemical neuroscience, 14, 3588-3598. doi:10.1021/acschemneuro.3c00392. https://pubmed.ncbi.nlm.nih.gov/37702025/

2. Li, Haidi, Chen, Xin, Xu, Jiejie, Meng, Xiao-Ming, Li, Jun. 2023. GRP/GRPR enhances alcohol-associated liver injury through the IRF1-mediated Caspase-1 inflammasome and NOX2-dependent ROS pathway. In Hepatology (Baltimore, Md.), 79, 392-408. doi:10.1097/HEP.0000000000000531. https://pubmed.ncbi.nlm.nih.gov/37409771/

3. Sun, Hao-Lu, Ma, Qiu-Ying, Bian, He-Ge, Meng, Xiao-Ming, Jin, Juan. 2023. Novel insight on GRP/GRPR axis in diseases. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 161, 114497. doi:10.1016/j.biopha.2023.114497. https://pubmed.ncbi.nlm.nih.gov/36933382/

4. Sun, Hao-Lu, Bian, He-Ge, Liu, Xue-Mei, Meng, Xiao-Ming, Jin, Juan. 2023. GRP/GRPR signaling pathway aggravates hyperuricemia-induced renal inflammation and fibrosis via ABCG2-dependent mechanisms. In Biochemical pharmacology, 218, 115901. doi:10.1016/j.bcp.2023.115901. https://pubmed.ncbi.nlm.nih.gov/38084678/

5. Li, Chao, Ma, Qiu-Ying, Liu, Xue-Qi, Yao, Ri-Sheng, Meng, Xiao-Ming. 2023. Genetic and pharmacological inhibition of GRPR protects against acute kidney injury via attenuating renal inflammation and necroptosis. In Molecular therapy : the journal of the American Society of Gene Therapy, 31, 2734-2754. doi:10.1016/j.ymthe.2023.06.016. https://pubmed.ncbi.nlm.nih.gov/37415332/